Chemical Biology & Drug Design

Abstract

Plasmepsin II (PlmII) is an aspartic protease of the plasmepsin family expressed in the food vacuole of the Plasmodium falciparum (Pf) that cleaves hemoglobin of the host during the erythrocytic stage of the parasite life cycle. Various peptidomimetic inhibitors of PlmII reported so far, discriminate poorly between the PlmII drug target and the proteases of the host organism e.g. Cathepsin D (CatD), an aspartic protease present in the mammalian cells, displaying thus insufficient selectivity. In this paper, intermolecular interactions of a series of inhibitors of PlmII containing a modified statine core has been modeled taking advantage of the crystal structure of the PlmII in complex with peptidomimetic inhibitor at the binding site, with the goal to gain insight into the structural requirements for PlmII specificity. The studied series of inhibitors was modeled at the active site of PlmII and CatD in order to establish quantitative structure-activity relationships (QSAR) models of the proteases inhibition and understand inhibitor-enzyme interactions underlying the target selectivity. In addition, 3D QSAR pharmacophore models of inhibitory activity towards each enzyme were generated. From the mode of binding of the studied inhibitors at the active site of PlmII and CatD we identified key structural features related to the protease selectivity. In particular, contribution of the P2 and P3’ residues of the inhibitor to the protease binding affinity were mainly responsible for the selectivity enhancement towards the CatD. Based on this knowledge, a handful of new inhibitor candidates was designed with predicted inhibitory activity towards PlmII Kipre reaching 0.2 nM and predicted selectivity index Kipre[CatD]/Kipre[PlmII] larger than 1200.